Observations at autopsy and animal investigations reveal a positive correlation between physical activity and coronary artery cross-sectional area. Work from our cardiac catheterization laboratory strongly supports a correlation between exercise intensity and coronary artery diameter. We therefore propose that exercise induces changes in structure and/or reactivity of human coronary arteries. We further hypothesize that exercise-induced vascular remodeling and reactivity is initiated by paracrine factors released by the endothelium in response to increases in coronary blood flow. To examine these hypotheses we will employ parallel human and animal studies to understand the fundamental mechanisms of these exercise-induced changes. Intravascular ultrasound and quantitative angiography will be used to prospectively document exercise-induced changes in coronary artery structure and reactivity in patients with mild coronary artery disease. By using these techniques we will determine the endothelial and vascular smooth muscle contributions to changes in vascular reactivity. We will further characterize the exercise-induced changes in vascular structure by measuring cross-sectional areas of the lumen, intima, and media. To elucidate the fundamental mechanisms of these exercise- induced changes we will study an animal model (the exercising rat), using a combination of molecular and physiological techniques. The relative contribution of the endothelium and the vascular smooth muscle to changes in vascular reactivity will be determined. We will elucidate the cellular mechanisms that mediate the vascular remodeling and determine the role of specific paracrine factors as mediators of this response. Finally, the role of blood flow and the endothelium in initiating these vascular changes will be defined. These studies will provide clinically relevant information regarding the effects of exercise on coronary artery tone and structure in humans and animals. They will delineate the mechanisms by which the blood vessel adapts to an important physiologic stimulus.